Pharmaceutical Research

, Volume 32, Issue 1, pp 222–237 | Cite as

Screening Methodologies for the Development of Spray-Dried Amorphous Solid Dispersions

  • Íris Duarte
  • José Luís Santos
  • João F. Pinto
  • Márcio Temtem
Research Paper



To present a new screening methodology intended to be used in the early development of spray-dried amorphous solid dispersions.


A model that combines thermodynamic, kinetic and manufacturing considerations was implemented to obtain estimates of the miscibility and phase behavior of different itraconazole-based solid dispersions. Additionally, a small-scale solvent casting protocol was developed to enable a fast assessment on the amorphous stability of the different drug-polymer systems. Then, solid dispersions at predefined drug loads were produced in a lab-scale spray dryer for powder characterization and comparison of the results generated by the model and solvent cast samples.


The results obtained with the model enabled the ranking of the polymers from a miscibility standpoint. Such ranking was consistent with the experimental data obtained by solvent casting and spray drying. Moreover, the range of optimal drug load determined by the model was as well consistent with the experimental results.


The screening methodology presented in this work showed that a set of amorphous formulation candidates can be assessed in a computer model, enabling not only the determination of the most suitable polymers, but also of the optimal drug load range to be tested in laboratory experiments. The set of formulation candidates can then be further fine-tuned with solvent casting experiments using a small amount of API, which will then provide the decision for the final candidate formulations to be assessed in spray drying experiments.

Key Words

Amorphous solid dispersion miscibility screening method solvent casting spray drying 



Amorphous solid dispersion(s)


Spray dried dispersion(s)




Solvent casting


Spray drying


Hydroxypropyl methylcellulose acetate succinate (grade MG)


Polyvinylpyrrolidone-vinyl acetate copolymer

Eudragit® EPO

Copolymer of dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate


Glass transition temperature



Íris Duarte would like to thank the financial support from Hovione Farmaciência SA and from Fundação para a Ciência e Tecnologia through the doctoral grant BDE/51422/2011.

Supplementary material

11095_2014_1457_MOESM1_ESM.docx (6 mb)
ESM 1 (5.99 mb)


  1. 1.
    Lipp R. The Innovator Pipeline: Bioavailability Challenges and Advanced Oral Drug Delivery Opportunities. American Pharmaceutical Review. 2013;16(3).Google Scholar
  2. 2.
    Thayer AM. Finding Solutions: Custom Manufacturers Take On Drug Solubility Issues To Help Pharmaceutical Firms Move Products Through Development. Chem Eng News. 2010;88(22):13–8.CrossRefGoogle Scholar
  3. 3.
    Perrie Y, Rades T. Pharmaceutics - Drug Delivery and Targeting: Pharmaceutical Press; 2010.Google Scholar
  4. 4.
    Smithey D, Gao P, Taylor L. Amorphous solid dispersions: An enabling formulation technology for oral delivery of poorly water soluble drugs. AAPS Newsmagazine. 2013;16(1):11–4.Google Scholar
  5. 5.
    Newman A, Knipp G, Zografi G. Assessing the Performance of Amorphous Solid Dispersions. J Pharm Sci. 2012;101:1355–77.PubMedCrossRefGoogle Scholar
  6. 6.
  7. 7.
    Janssens S, Van den Mooter G. Review: physical chemistry of solid dispersions. J Pharm Pharmacol. 2009;61:1571–86.PubMedCrossRefGoogle Scholar
  8. 8.
    Van den Mooter G. The use of amorphous solid dispersions: A formulation strategy to overcome poor solubility and dissolution rate. Drug Discovery Today: Technologies. 2012;9(2):e79–85.CrossRefGoogle Scholar
  9. 9.
    Marsac P, Shamblin S, Taylor LS. Theoretical and practical approaches for prediction of drug-polymer miscibility and solubility. Pharm Res. 2006;23(10):2417–26.PubMedCrossRefGoogle Scholar
  10. 10.
    Tian Y, Booth J, Meehan E, Jones DS, Li S, Andrews P. Construction of Drug−Polymer Thermodynamic Phase Diagrams Using Flory−Huggins Interaction Theory: Identifying the Relevance of Temperature and Drug Weight Fraction to Phase Separation within Solid Dispersions. Mol Pharm. 2013;10:236–48.PubMedCrossRefGoogle Scholar
  11. 11.
    Tian Y, Caron V, Jones DS, Healy AM, Andrews GP. Using Flory-Huggins phase diagrams as a pre-formulation tool for the production of amorphous solid dispersions: a comparison between hot-melt extrusion and spray drying. J Pharm Pharmacol. 2014;66(2):256–74.PubMedCrossRefGoogle Scholar
  12. 12.
    Zhao Y, Inbar P, Chokshi HP, Malick AW, Choi DS. Prediction of the thermal phase diagram of amorphous solid dispersions by Flory-Huggins theory. J Pharm Sci. 2011;100(8):3196–207.PubMedCrossRefGoogle Scholar
  13. 13.
    Paudel A, Nies E, Van den Mooter G. Relating hydrogen-bonding interactions with the phase behavior of naproxen/PVP K 25 solid dispersions: Evaluation of solution-casted and quench-cooled films. Mol Pharm. 2012;9(11):3301–17.PubMedCrossRefGoogle Scholar
  14. 14.
    Bellantone RA, Patel P, Sandhu H, Choi DS, Singhal D, Chokshi H, et al. A Method to Predict the Equilibrium Solubility of Drugs in Solid Polymers near Room Temperature Using Thermal Analysis. J Pharm Sci. 2012;101(12):4549–58.PubMedCrossRefGoogle Scholar
  15. 15.
    Kyeremateng SO, Pudlas M, Woehrle GH. A Fast and Reliable Empirical Approach for Estimating Solubility of Crystalline Drugs in Polymers for Hot-Melt Extrusion Formulations. Journal of Pharmaceutical Sciences. 2014.Google Scholar
  16. 16.
    Mahieu A, Willart JF, Dudognon E, Danède F, Descamps. A new protocol to determine the solubility of drugs into polymer matrixes. Mol Pharm. 2013;10(2).Google Scholar
  17. 17.
    Tao J, Sun Y, Zhang GGZ, Yu L. Solubility of Small-Molecule Crystals in Polymers: D-Mannitol in PVP, Indomethacin in PVP/VA, and Nifedipine in PVP/VA. Pharm Res. 2009;26(4).Google Scholar
  18. 18.
    Greenhalgh DJ, Willimans AC, Timmins P, York P. Solubility parameters as predictors of miscibility in solid dispersions. J Pharm Sci. 1999;88(11):1182–90.PubMedCrossRefGoogle Scholar
  19. 19.
    Forster A, Hempenstall J, Tucker I, Rades. Selection of excipients for melt extrusion with two poorly water-soluble drugs by solubility parameter calculation and thermal analysis. Int J Pharm. 2001;226:147–61.PubMedCrossRefGoogle Scholar
  20. 20.
    Marsac PJ, Rumondor AC, Nivens DE, Kestur US, Stanciu L, Taylor LS. Effect of Temperature and Moisture on the Miscibility of Amorphous Dispersions of Felodipine and Poly(vinyl pyrrolidone). J Pharm Sci. 2010;99(1):169–85.PubMedCrossRefGoogle Scholar
  21. 21.
    Albers J, Matthée K, Knop K, Kleinebudde P. Evaluation of predictive models for stable solid solution formation. 2011;100(2):667–80.Google Scholar
  22. 22.
    Keen JM, Martin, Machado A, Sandhu, McGinity JW, DiNunzio JC. Investigation of process temperature and screw speed on properties of a pharmaceutical solid dispersion using corotating and counter-rotating twin-screw extruders. J Pharm Pharmacol. 2014;66(2):204–17.PubMedCrossRefGoogle Scholar
  23. 23.
    Saylor DM, Kim CS, Patwardhan DV, Warren JA. Diffuse-interface theory for structure formation and release behavior in controlled drug release systems. Acta Biomater. 2007;3:851–64.PubMedCrossRefGoogle Scholar
  24. 24.
    Saylor DM. Predicting Microstructure Evolution in Controlled Drug Release Coatings. In FDA/NHLBI/NSF Workshop on Computer Methods for Cardiovascular Devices ; 2010; USA.Google Scholar
  25. 25.
    Guyer JE, Wheeler D, Warren JA. FiPy:Partial Differential Equations with Python. Computing in Science & Engineering. 2009;11(3):6–15.CrossRefGoogle Scholar
  26. 26.
    Krevlen DW. Nijenhuis Kt. Properties of Polymers Amsterdam: Elsevier; 2009.Google Scholar
  27. 27.
    Lin D, Huang Y. A thermal analysis method to predict the complete phase diagram of drug-polymer solid dispersions. Int J Pharm. 2010;399(1–2):109–15.PubMedCrossRefGoogle Scholar
  28. 28.
    Kawakami K, Hasegawa Y, Deguchi K, Ohki S, Shimizu T, Yoshihashi Y, et al. Competition of Thermodynamic and Dynamic Factors During Formation of Multicomponent Particles via Spray Drying. J Pharm Sci. 2013;102(2):518–29.PubMedCrossRefGoogle Scholar
  29. 29.
    Wilke CR, Chang P. Correlation of diffusion coeficients in dilute solutions. AIChE Journal. 1955;: p. 264-270.Google Scholar
  30. 30.
    Masters K. Spray Drying in Practice Denmark: SprayDry Consult. 2002.Google Scholar
  31. 31.
    Goula AM, Adamopoulos KG. Influence of Spray Drying Conditions on Residue Accumulation - Simulation Using CFD. Dry Technol. 2004;22(5):1107–28.CrossRefGoogle Scholar
  32. 32.
    Poling BE, Prausnitz JM. O'Connell JP. The Properties of Gases and Liquids: McGraw-Hill; 2001.Google Scholar
  33. 33.
    Miller RS, Harstad K, Bellan J. Evaluation of equilibrium and non-equilibrium evaporation models for many-droplet gas-liquid flow simulations. Int J Multiphase Flow. 1998;24:1025–55.CrossRefGoogle Scholar
  34. 34.
    Paudel A, Humbeeck JV, Van den Mooter G. Theoretical and Experimental Investigation on the Solid Solubility and Miscibility of Naproxen in Poly(vinylpyrrolidone). Mol Pharm. 2010;7(4):1133–48.PubMedCrossRefGoogle Scholar
  35. 35.
    Baird JA, Taylor LS. Evaluation of amorphous solid dispersion properties using thermal analysis techniques. Adv Drug Deliv Rev. 2012;64(5):396–421.PubMedCrossRefGoogle Scholar
  36. 36.
    Six K, Verreck G, Peeters, Binnemans, Berghmans, Augustijns, et al. Investigation of thermal properties of glassy itraconazole: identification of a monotropic mesophase. Thermochim Acta. 2001;376:175–81.CrossRefGoogle Scholar
  37. 37.
    Fedors RF. A Method for Estimating Both the Solubility Parameters and Molar Volumes of liquids. Polym Eng Sci. 1974;14(2):147–54.CrossRefGoogle Scholar
  38. 38.
    Barton AFM. Handbook of Solubility Parameters and Other Cohesion Parameters Florida: Boca Raton, CRC Press; 1983Google Scholar
  39. 39.
    Janssens S, de Armas N, Autry D, Van S, den Mooter V. Characterization of ternary solid dispersions of Itraconazole in polyethylene glycol 6000/polyvidone-vinylacetate 64 blends. Eur J Pharm Biopharm. 2008;69:1114–20.PubMedCrossRefGoogle Scholar
  40. 40.
    Marsac PJ, Li T, Taylor LS. Estimation of drug polymer miscibility and solubility in amorphous solid dispersions using experimentally determined interaction parameters. Pharm Res. 2009;26(1):139–51.PubMedCrossRefGoogle Scholar
  41. 41.
    Six K, Verreck G, Peeters J, Brewster M, Van den Mooter G. Increased Physical Stability and Improved Dissolution Properties of Itraconazole, a Class II Drug, by Solid Dispersions that Combine Fast- and Slow-Dissolving Polymers. J Pharm Sci. 2004;93(1):124–31.PubMedCrossRefGoogle Scholar
  42. 42.
    Marsac PJ, Li T, Taylor LS. Estimation of drugpolymer miscibility and solubility in amorphous solid dispersions using experimentally determined interaction parameters. Pharm Res. 2009;26(1):139–51.PubMedCrossRefGoogle Scholar
  43. 43.
    Overhoff, Moreno A, Miller DA, Johnston P, Williams III RO. Solid dispersions of itraconazole and enteric polymers made by ultra-rapid freezing. Int J Pharm. 2007;336:122–32.PubMedCrossRefGoogle Scholar
  44. 44.
    Rumondor CF, Wikström H, Eerdenbrugh V, Taylor LS. Understanding the Tendency of Amorphous Solid Dispersions to Undergo Amorphous–Amorphous Phase Separation in the Presence of Absorbed Moisture. AAPS PharmSciTech. 2011;12(4):1209–19.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Janssens S, Nagels S, de Novoa HA, Van Schepdael A, Van den Mooter G. Formulation and characterization of ternary solid dispersions made up of Itraconazole and two excipients, TPGS 1000 and PVPVA 64, that were selected based on a supersaturation screening study. Eur J Pharm Biopharm. 2008;69:158–66.PubMedCrossRefGoogle Scholar
  46. 46.
    Vasanthavada M, Tong WQ, Joshi, Kislalioglu. Phase Behavior of Amorphous Molecular Dispersions I: Determination of the Degree and Mechanism of Solid Solubility. Pharm Res. 2004;21(9):1598–606.PubMedCrossRefGoogle Scholar
  47. 47.
    van Drooge DJ, Hinrichs WLJ, Visser MR, Frijlink HW. Characterization of the molecular distribution of drugs in glassy solid dispersions at the nano-meter scale, using differential scanning calorimetry and gravimetric water vapour sorption techniques. Int J Pharm. 2006;310:220–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Pharmaceutical Development. ICHQ8(R2). Geneva: International Conference on Harmonisation; 2009.Google Scholar
  49. 49.
    Janssens S, Zeure AD, Paudel A, Humbeeck JV, Rombaut P, Van den Mooter G. Influence of Preparation Methods on Solid State Supersaturation of Amorphous Solid Dispersions: A Case Study with Itraconazole and Eudragit E100. Pharm Res. 2010;27(5):775–85.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Íris Duarte
    • 1
    • 2
  • José Luís Santos
    • 2
  • João F. Pinto
    • 1
  • Márcio Temtem
    • 2
  1. 1.iMed – Research Institute for Medicines and Pharmaceutical SciencesUniversity of Lisbon, Faculty of PharmacyLisboaPortugal
  2. 2.R&D Drug Product DevelopmentHovione Farmaciência SALouresPortugal

Personalised recommendations